Various scientific and scholarly articles are referred to in brackets throughout the specification.
These articles are incorporated by reference herein to describe the state of the art to which this invention pertains.
Prostate cancer has the highest incidence of male cancers in the U.S. However, the molecular mechanisms underlying prostate carcinogenesis that may lead to new therapeutic treatments remain enigmatic. Tyrosine phosphorylation signaling in prostate cell proliferation is mediated by PTPases. Recently, several lines of evidence have suggested that cellular PAcP represents the major PTPase activity in prostate epitheliums (Lin and Clinton, 1987, Advances in Protein Phosphatases 4:199–228; Li et al., 1984, Eur. J. Biochem. 138:45–51; Lin and Clinton, 1986, Biochem. J., 235:351–357). This notion is further supported by results from crystallographic studies (Schneider et al., 1993, EMBO J. 12:2609–2615) and titration experiments (Ostanin et al. 1994, J. Biol. Chem. 269:8971–8978), indicating that PAcP protein has active “-SH” groups and can function as an authentic “cysteine” PTPase in those cells.
Two forms of PAcP exist in normal human prostate epithelial cells. One form is secreted and the other is intracellular. In normal differentiated prostate epitheliums, the expression of the cellular form of human PAcP is correlated with slow proliferation of those cells (Lin and Clinton, 1987, Advances in Protein Phosphatases 4:199–228; Sakai et al., 1993, J. Urol. 149:1020–1023; Sinha et al., 1998, The Prostate, 13:1–15). Increased cellular PAcP activity is coincident with decreased p-Tyr levels in cellular proteins and a slow growth rate (Lin et al., 1992 Cancer Res., 52:4600–4607; Lin et al., 1993, Biophys. Biochem. Res. Comm. 192:413–419; Lin et al., 1994, Differentiation, 57:143–149).
In prostate carcinomas exhibiting high proliferation rates, cellular PAcP expression is decreased (Lin and Clinton, 1987, Advances in Protein Phosphatases 4:199–228; Sakai et al., 1993, J. Urol. 149:1020–1023; Sinha et al., 1998, The Prostate, 13:1–15). The secreted form of PAcP increases in abundance in prostate cancer patient circulation, which has led to its use as a diagnostic marker. Treatment with growth stimuli, including androgens, on cell from the human prostatic cancer cell line LNCaP results in decreased cellular PAcP activity and increased cellular growth (Lin et al., 1992 Cancer Res., 52:4600–4607). Since PAcP is a classically known androgen-responsive enzyme (Lin and Clinton, 1987, Advances in Protein Phosphatases 4:199–228), the cellular form of PAcP may participate in androgen promotion of cell proliferation via a tyrosine phosphorylation pathway (Lin et al., 1998, J. Biol. Chem. 273:5939–5947).
Development and maintenance of differentiated function of the normal prostate gland require androgen (Tenniswood, 1986, Prostate 9:375–385). Androgen has also been implicated in the carcinogenesis of prostate epithelium (Gyorkey, 1973, Methods Cancer Res. 10:279–368; Gittes, 1991, N. Eng. J. Med. 324;236–245). This is evidenced by observations that, at least in the early phase of prostate carcinogenesis, the growth of carcinoma cells can be stimulated by androgen and arrested by androgen withdrawal (Huggins and Hodges, 1941, Cancer Res. 1:293–297). Thus, hormonal manipulation including anti-androgen and androgen deprivation therapy is the predominant treatment of advanced cancer, being approximately 70% effective (Gittes, 1991, N. Eng. J. Med. 324:236–245; Scott et al., 1980, Cancer 45:1929–1936; Grayhack et al., 1987, Cancer 60:589–601). Hormone therapy, however, is not curative, and disease relapse will inevitably occur, usually within 24 months (Gittes, 1991, N. Eng. J. Med. 324:236–245). The molecular mechanism(s) underlying this transition from androgen-responsive to androgen-unresponsive prostate cancer is not understood, slowing the development of effective treatments.
In the past few years, several new approaches including gene therapy for treating advanced cancer have been proposed. Since the differential expression of a desired product in the target tissue is the central to the concept of gene therapy, several strategies for targeting specific gene expression have been developed. One such approach is to use a tissue-specific promoter to drive therapeutic genes (Pang et al., 1997, Cancer. Res. 57:495–499; Cleutjens et al., 1997, Mol. Endocrinol. 11:1256–1265; Cleutjens et al., 1997, Mol. Endocrinol. 11:148–161). Because a tissue-specific promoter can only be activated in the targeted tissue, the genes driven by the promoter will be expressed differentially in these cells, minimizing systemic toxicity. In regard to prostate cancer, the promoter of the Prostate Specific Antigen gene (PSA) is a possible candidate serving for that approach. However, the expression of the PSA gene is not specific only to the prostate. Its expression was observed in several breast tumors and endometrium (Shan et al., 1997, Endocrinology 138:3764–3770).
PAcP has a long history of serving as a tumor marker of prostate cancer and has been proposed to have a tissue-specific manner of expression (Chu et al., 1982, in Biochemical Markers of Cancer, Chu, Ed., pp. 117–136, Dekker, New York; Lin and Clinton, 1987, Adv. Prot. Phosphatase 4:199–228). Nevertheless, controversial results exist (Yam et al., 1982, Ann. New York Academy Sci. 390:73–88). Although DNA sequences of PAcP promoter have been reported (Virkkunen et al., 1994, Biochem. Biophys. Res. Commun. 202:49–57; Banas et al., 1994, Biochim. Biophys. Acta 1217:188–194; Sharief and Li, 1994, Biochem. Mol. Biol. Int. 33:561–565), no information is yet available on regulation of the promoter activity of PAcP gene in human prostatic cancer cells and other organs and tissues.
In order to develop effective and novel treatments and diagnosis for prostate cancer, novel biochemical targets for manipulation are needed. Of most urgent need are targets that can be used to diagnose and therapeutically treat the later stage androgen-resistant cancers. To further an variety of potential treatment methods, promoters that are specific to prostate cells are needed to allow gene therapy methods. These specific promoters may also be used to enhance diagnosis and research into prostate cancer disease.